A Notch-Dependent Inflammatory Feedback Circuit between Macrophages and Cancer Cells Regulates Pancreatic Cancer Metastasis

Abstract Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between cancer cells and macrophages, which contributes to metastasis. circuit, miR-124 regulated signaling by directly targeting the ligand Jagged 1. Autoamplified promoted recruitment of macrophages tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1α, uPA paracrine signaling. turn, activated macrophage-derived IL6 oncogenic transcription factor STAT3 that repressed genes conserved STAT3-binding site their promoters, thereby promoting cell epithelial–mesenchymal transition invasion. Disrupting suppressed liver mouse models. Thus, our study suggests manipulation therapeutic potential for treatment Significance: This provided targets robust preclinical evidence interrupting with targeted inhibitors.